The aim of this proposal is to use retroviral vectors to direct the expression of the leukocyte integrin CD18 subunit in vitro in peripheral blood progenitor and bone marrow cells from normal individuals and from children with leukocyte adherence deficiency or LAD, and in vivo in bone marrow cells from mice in which the CD18 has been disrupted by gene targeting. Children with LAD experience recurrent, life-threatening bacterial infections due to the inability of the leukocytes from these children to adhere to the vessel wall and migrate to the site of infection. The clinical manifestations of the disease stem from the inability of leukocytes from children with LAD to express the members of the leukocyte integrin CD11/CD18 molecules on the cell surface due to defects in the CD18 subunit. Leukocyte adherence deficiency is a candidate disease for human gene therapy based upon gene transfer into hematopoietic progenitor cells and stem cells in that: l) the disease is life-threatening in the severe deficiency form, 2) except for bone marrow transplantation there is no treatment other than supportive therapy, 3) transduction of a normal CD18 gene into LAD EBV B-cells has been shown to correct the biochemical and functional defect, and 4) based upon gene expression by leukocytes in the moderate deficiency phenotype of LAD, 5% of normal levels of CD11/CD18 expression appears to be sufficient to correct the severe clinical manifestations of the disease. The current studies are designed to determine the optimal conditions for using retroviral vectors to restore CD18 expression in peripheral blood progenitors and bone marrow cells from LAD children with the ultimate goal of long-term disease correction by CD18 gene transfer into hematopoietic stem cells. In these studies we aim to: 1) determine the conditions required for retroviral vectors LgCD18SN and LgCD18, encoding the human CD18 subunit, to produce high efficiency gene transduction and gene expression of the CD18 subunit in peripheral blood progenitor cells and bone marrow cells from normal individuals and from children with LAD; 2) to determine the efficacy, efficiency, and safety of transduction of the human CD18 subunit into bone marrow cells from mice in whom the CD18 subunit has been disrupted by gene targeting. LAD is an attractive model for human gene therapy in that transduction of peripheral blood progenitor cells and bone marrow cells with CD18-encoding vectors ex vivo followed by re-infusion of the transduced cells may be major therapeutic benefit to children with LAD. During acute episodes of infection the granulocytes and monocytes which differentiate from the CD18-transduced progenitor cells may traffic to the inflammatory site and participate in the host response to the infectious agent. Thus, transduction of a hematopoietic stem cell may not be required for a clinical response in LAD.